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Recent Publications by VICC Researchers

June 22, 2011

Vanderbilt-Ingram Cancer Center is committed to conducting innovative, high-impact basic, translational and clinical research with the greatest potential for making a difference for cancer patients, today and in the future. Here’s a sampling of recent work published in peer-reviewed journals by center investigators:

Weight’s impact on death risk

Asians of normal weight are far less likely to die from any cause – including cancer and cardiovascular disease – than individuals with a body-mass index (BMI) that is too high or low, according to a study led by Wei Zheng, M.D., Ph.D., MPH, and colleagues. They found that, among East Asians – including Chinese, Japanese and Koreans – the lowest risk of death was seen among individuals with a BMI ranging from 22.6 to 27.5 (considered normal to slightly overweight). East Asians with a BMI of 35 or higher had a 50 percent higher risk of death. Risk of death was also increased by a factor of 2.8 among severely underweight individuals (whose BMI was 15.0 or less). The results, reported Feb. 24 in the New England Journal of Medicine, provide strong evidence that excess weight contributes to a higher risk of death.

Paths to melanoma drug resistance

About 50 percent of all melanomas harbor B-RAF mutations, and the investigational drug PLX4032 shows an 80 percent response rate in such tumors. However, many tumors become resistant to the drug. Jeffrey Sosman, M.D., and colleagues from two other institutions recently identified molecular pathways that allow metastatic melanoma tumors with B-RAF mutations to develop resistance to this drug. The study, published in the Dec. 16 issue of Nature, showed that drug resistance develops through at least two different molecular mechanisms that activate survival pathways for the cancer cells – overexpression of a cell surface protein (PDGFRß) or mutation in a second oncogene (N-RAS). Identification of these pathways can inform the search for additional drugs that may provide therapeutic strategies for melanoma patients who develop resistance to the B-RAF drugs, the authors conclude.

Chromatin clues about cancer drugs

Proteins called HDACs are the targets of a new class of anti-cancer compounds (HDAC inhibitors), but how these compounds kill tumor cells – and the potential side effects of such drugs – remains unclear. Scott Hiebert, Ph.D., Srividya Bhaskara, Ph.D., and colleagues have discovered that mice missing a particular HDAC (HDAC3) in the liver have disrupted chromatin – the compacted form of DNA in the cell nucleus – and develop liver cancer. The team’s findings, reported in the Nov. 16 issue of Cancer Cell, offer insights into HDAC inhibitor function and suggest ways to use the compounds more effectively. Such information on the function of other individual HDACs will be needed to design better and more specific cancer therapeutics, since two recently approved HDAC inhibitors, vorinostat (Zolinza) and romidepsin (Istodax), block more than one type of HDAC.

Strong social ties benefit survivors

Breast cancer patients with a strong social support system in the first year after diagnosis are less likely to die or have a recurrence of cancer, according to a study by Meira Epplein, Ph.D., Xiao Ou Shu, M.D., Ph.D., and colleagues. The researchers found that, among breast cancer survivors enrolled in the Shanghai Breast Cancer Survivor Study, women reporting the highest levels of social well-being had a 48 percent reduction in their risk of a cancer recurrence and a 38 percent reduction in the risk of death. However, the association tapered off and was no longer statistically significant by the third year after diagnosis. The results, reported in the Feb. 1 Journal of Clinical Oncology, suggest that interventions to maintain or enhance social support soon after diagnosis could improve disease outcomes.

Targeting lung cancer in never-smokers

Between 10 percent and 15 percent of new lung cancer cases arise in never-smokers, who – along with East-Asians and individuals with adenocarcinoma tumors – appear more likely to respond to certain targeted therapies. To investigate genetic factors underlying this response, William Pao, M.D., Ph.D., and colleagues analyzed major known “driver mutations” – mutations in genes involved in cell proliferation and survival – in lung adenocarcinomas from 52 Chinese patients classified as never-smokers. The investigators found that 88 percent of tumors harbored well-known mutations in EGFR, HER2 or ALK – all of which have corresponding targeted therapies now available. The results in the Oct. 20 issue of the Journal of Clinical Oncology indicate that prospective genetic testing in these patients would allow for the selection of an appropriate targeted therapy in most cases.

Frog egg extracts yield colon cancer drug lead

More than 90 percent of sporadic (non-inherited) colon cancers are caused by mutations that result in inappropriate activation of the Wnt signaling pathway. Blocking this pathway has been a desirable therapeutic target, but its complexity has made it difficult to determine which molecular participants to inhibit. Ethan Lee, M.D., Ph.D., and colleagues used frog egg extracts to screen several thousand chemical compounds for their ability to modify Wnt signaling. In the November issue of Nature Chemical Biology, they report that an old pinworm medicine – pyrvinium – blocks Wnt signaling in this system and inhibits cell proliferation in cultured colon cancer cells. The researchers also identified the enzyme target of pyrvinium – casein kinase 1alpha – which could provide a new target for colon cancer therapies.